CD123 expression patterns and selective targeting with a CD123-targeted antibody-drug conjugate (IMGN632) in acute lymphoblastic leukemia

Haematologica. 2019 Apr;104(4):749-755. doi: 10.3324/haematol.2018.205252. Epub 2018 Oct 25.

Abstract

The potential of CD123-targeted therapies in acute lymphoblastic leukemia/lymphoma remains largely unexplored. We examined CD123 expression levels in a large cohort of patients with acute lymphoblastic leukemia/lymphoma and assessed the in vitro impact of IMGN632, a conjugate of CD123-binding antibody with a novel DNA-alkylating payload. CD123 expression on leukemic blasts was surveyed using multicolor/multiparameter flow cytometry. The in vitro effect of IMGN632 was evaluated on B acute lymphoblastic leukemia/lymphoma cell lines and primary B acute lymphoblastic leukemia/lymphoma blasts. The study cohort (n=213) included 183 patients with B acute lymphoblastic leukemia/lymphoma and 30 with T acute lymphoblastic leukemia/lymphoma. CD123 expression was more prevalent in B acute lymphoblastic leukemia/lymphoma than in T acute lymphoblastic leukemia/lymphoma (164/183, 89.6% versus 13/30, 43.3%; P<0.0001), and within B acute lymphoblastic leukemia/lymphoma CD123 expression was more prevalent in Philadelphia chromosome-positive patients than in Philadelphia chromosome-negative patients (96.6% versus 86.3%; P=0.033). In T acute lymphoblastic leukemia/lymphoma, 12/13 (92.3%) patients with CD123-positive blasts had either early T precursor (ETP) or early non-ETP immunophenotype. IMGN632 was highly cytotoxic to B acute lymphoblastic leukemia/lymphoma cell lines, with half maximal inhibitory concentrations (IC50) between 0.6 and 20 pM. In five of eight patients' samples, low picomolar concentrations of IMGN632 eliminated more than 90% of the B acute lymphoblastic leukemia/lymphoma blast population, sparing normal lymphocytes. In conclusion, CD123 expression is prevalent across acute lymphoblastic leukemia/lymphoma subtypes, and the CD123-targeted antibody-drug conjugate IMGN632 demonstrates promising selective activity in preclinical models of B acute lymphoblastic leukemia/lymphoma.

Publication types

  • Clinical Trial

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Immunological / pharmacology*
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • Drug Delivery Systems*
  • Female
  • Gene Expression Regulation, Leukemic / drug effects*
  • Humans
  • Immunoconjugates / pharmacology*
  • Infant
  • Interleukin-3 Receptor alpha Subunit* / antagonists & inhibitors
  • Interleukin-3 Receptor alpha Subunit* / biosynthesis
  • Male
  • Middle Aged
  • Neoplasm Proteins* / antagonists & inhibitors
  • Neoplasm Proteins* / biosynthesis
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma* / metabolism
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma* / pathology
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / metabolism
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / pathology

Substances

  • Antineoplastic Agents, Immunological
  • IL3RA protein, human
  • Immunoconjugates
  • Interleukin-3 Receptor alpha Subunit
  • Neoplasm Proteins